ALBERT

Description: Conservation of genetic resources is of great concern globally to maintain genetic diversity for sustainable food security. Comprehensive identification of the breed composition, estimation of inbreeding and effective population size are essential for the effective management of farm animal genetic resources and to prevent the animals from genetic erosion. The Zhongwei male (ZWM), Arbas Cashmere male (ACM) and Jining Grey male (JGM) goats are conserved in three different state goat farms in China but their family information, level of inbreeding and effective population size are unknown. We investigated the genomic relationship, inbreeding coefficient and effective population size in these three breeds from three state goat farms using the Illumina goat SNP50 BeadChip. Genomic relationships and phylogenetic analysis revealed that the breeds are clearly separated and formed separate clusters based on their genetic relationship. We obtained a high proportion of informative SNPs, ranging from 91.8% in the Arbas Cashmere male to 96.2% in the Jining Grey male goat breeds with an average mean of 96.8%. Inbreeding, as measured by FROH, ranged from 1.79% in ZWM to 8.62% in ACM goat populations. High FROH values, elevated genomic coverage of very long ROH (〉30 Mb) and severe decline in effective population size were recorded in ACM goat farm. The existence of a high correlation between FHOM and FROH indicates that FROH can be used as an alternative to inbreeding estimates in the absence of pedigree records. The Ne estimates 13 generations ago were 166, 69 and 79 for ZWM, ACM and JGM goat farm, respectively indicating that these goat breeds were strongly affected by selection pressure or genetic drift. This study provides insight into the genomic relationship, levels of inbreeding and effective population size in the studied goat populations conserved in the state goat farms which will be valuable in prioritizing populations for conservation and for developing suitable management practices for further genetic improvement of these Chinese male goats.

Description: Pectobacterium carotovorum is a gram-negative bacterium that, together with other soft rot Enterobacteriaceae causes soft rot disease in vegetables, fruits, and ornamental plants through the action of exoproteins including plant cell wall-degrading enzymes (PCWDEs). Although pathogenicity in these bacteria is complex, virulence levels are proportional to the levels of plant cell wall-degrading exoenzymes (PCWDEs) secreted. Two low enzyme-producing transposon Tn5 mutants were isolated, and compared to their parent KD100, the mutants were less virulent on celery petioles and carrot disks. The inactivated gene responsible for the reduced virulence phenotype in both mutants was identified as wcaG. The gene, wcaG (previously denoted fcl) encodes NAD-dependent epimerase/dehydratase, a homologue of GDP-fucose synthetase of Escherichia coli. In Escherichia coli, GDP-fucose synthetase is involved in the biosynthesis of the exopolysaccharide, colanic acid (CA). The wcaG mutants of P. carotovorum formed an enhanced level of biofilm in comparison to their parent. In the hydrophobicity test the mutants showed more hydrophobicity than the parent in hexane and hexadecane as solvents. Complementation of the mutants with extrachromosomal copies of the wild type gene restored these functions to parental levels. These data indicate that NAD-dependent epimerase/dehydratase plays a vital rule in cell surface properties, exoenzyme production, and virulence in P. carotovorum.

Description: Background: The outcome of patients (pts) with myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure is poor with a median overall survival (OS) of only 4-6 months; there is no standard of care in this setting. Omacetaxine mepesuccinate (OM) has previously been shown to be safe and effective in acute myeloid leukemia (AML), including in pts who progressed from MDS. We sought to evaluate the safety and efficacy of OM in pts with MDS after HMA failure. Methods: Adult pts with MDS or CMML who had not responded to, progressed on, or relapsed after HMA therapy were eligible for this study. Pts were required to be intermediate-2- or high-risk by IPSS or be classified as RAEB-1 (5-9% BM blasts), RAEB-2 (10-19% BM blasts) or CMML (5-19% BM blasts). Pts received OM 1.25 mg/m2 SQ every 12 hours x 3 days on a 28-day cycle. The primary efficacy outcomes were overall survival (OS) and the overall response rate (ORR), defined as the composite of complete remission (CR), partial remission (PR), marrow CR (mCR) and hematologic improvement (HI). Secondary outcomes included the remission duration, relapse-free survival (RFS), and the safety profile of the regimen. Results: Between 6/2015 and 7/2016, 24 pts have been treated. Baseline characteristics are summarized in Table 1. The median age of the cohort was 74 years (range, 61-86 years). The median BM blasts was 10% (range, 2-18%) and 10 pts (42%) had adverse karyotype. IPSS risk group was intermediate-1 in 6 pts (25), intermediate-2 in 13 (54%), and high in 5 (21%). Among 19 pts who underwent comprehensive mutation profiling, 17 (89%) had at least one molecular mutation identified. The most frequently identified mutations were RUNX1 in 8 pts (33%), TET2 in 7 (29%), ASXL1 in 6 (25%), TP53 in 6 (25%), and EZH2 in 4 (17%). The median duration of follow-up was 4 months (range, 1-13 months), and the median number of cycles of OM received was 3 (range, 1-10). The ORR was 29%; all 7 pts who responded to OM achieved mCR as best response; no pts achieved CR or HI. The median time to best response was 1.9 months (range, 1.1-5.7 months). Responses were seen across cytogenetic risk groups: 4 responders were diploid, 1 had complex karyotype, 1 had monosomy 7 and 1 had trisomy 8. The response rates for pts with diploid and adverse-risk cytogenetics were 50% and 20%, respectively (P=0.18). Of the 7 responders, 3 remain on study, 2 relapsed, and 2 died while on study. To date, 8 pts (33%) have died. The median OS was 8.2 months, and the 6-month OS rate was 67%. The median OS for pts with diploid and adverse-risk cytogenetics was not reached and 8.2 months, respectively (P=0.08). The median RFS was 3.4 months, and the 6-month RFS rate was 33%. Among the 2 pts who relapsed, the remission duration was 3.0 and 3.4 months. AML developed in 8 pts (33%) with a median time to AML of 2.3 months (range, 0.9-3.9 months). Treatment was overall well-tolerated. Among 17 pts who have received ≥2 courses of OM, 2 (12%) required dose reduction during subsequent cycles. Most adverse events were grade 1-2; grade ≥3 adverse events occurred in 8 pts (33%). The most frequent non-hematologic adverse events were fatigue in 12 pts (50%), nausea in 7 (29%), infection in 6 (25%), mouth sores in 5 (21%), and headache in 3 (13%). Five pts died while on study; the causes of death were sepsis/pneumonia (n=3), pneumonitis (n=1) and unknown cause (n=1). Conclusions: In pts with MDS who previously failed HMA therapy, OM was safe and resulted in an ORR of 29%. The median OS of 8.2 months compares favorably to the historical reports of survival post-HMA failure. Disclosures Konopleva: Cellectis: Research Funding; Calithera: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Description: Genome-wide linkage disequilibrium is a useful parameter to study quantitative trait locus (QTL) mapping and genetic selection. In many genomic methodologies, effective population size is an important genetic parameter because of its relationship to the loss of genetic variation, increases in inbreeding, the accumulation of mutations, and the effectiveness of selection. In this study, a total of 193 individuals were genotyped to assess the extent of LD and Ne in six Chinese goat populations using the SNP 50K BeadChip. Across the determined autosomal chromosomes, we found an average of 0.02 and 0.23 for r2 and D’ values, respectively. The average r2 between all the populations varied little and ranged from 0.055 r2 for the Jining Grey to 0.128 r2 for the Guangfeng, with an overall mean of 0.083. Across the 29 autosomal chromosomes, minor allele frequency (MAF) was highest on chromosome 1 (0.321) and lowest on chromosome 25 (0.309), with an average MAF of 0.317, and showing the lowest (25.5% for Louping) and highest (28.8% for Qingeda) SNP proportions at MAF values 〉 0.3. The inbreeding coefficient ranged from 0.064 to 0.085, with a mean of 0.075 for all the autosomes. The Jining Grey and Qingeda populations showed higher Ne estimates, highlighting that these animals could have been influenced by artificial selection. Furthermore, a declining recent Ne was distinguished for the Arbas Cashmere and Guangfeng populations, and their estimated values were closer to 64 and 95, respectively, 13 generations ago, which indicates that these breeds were exposed to strong selection. This study provides an insight into valuable genetic information and will open up the opportunity for further genomic selection analysis of Chinese goat populations.